EP1970072A1 - Utilisation de peptides GLP-2 pour le traitement d'hyperparathyroïdie - Google Patents
Utilisation de peptides GLP-2 pour le traitement d'hyperparathyroïdie Download PDFInfo
- Publication number
- EP1970072A1 EP1970072A1 EP08156283A EP08156283A EP1970072A1 EP 1970072 A1 EP1970072 A1 EP 1970072A1 EP 08156283 A EP08156283 A EP 08156283A EP 08156283 A EP08156283 A EP 08156283A EP 1970072 A1 EP1970072 A1 EP 1970072A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- glp
- bone
- peptide
- receptor
- bone resorption
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- 101800000221 Glucagon-like peptide 2 Proteins 0.000 title claims abstract description 77
- 238000011282 treatment Methods 0.000 title claims abstract description 12
- 201000002980 Hyperparathyroidism Diseases 0.000 title claims abstract description 6
- 102400000326 Glucagon-like peptide 2 Human genes 0.000 title claims 6
- TWSALRJGPBVBQU-PKQQPRCHSA-N glucagon-like peptide 2 Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(O)=O)C(O)=O)[C@@H](C)CC)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCSC)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CO)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)CC)C1=CC=CC=C1 TWSALRJGPBVBQU-PKQQPRCHSA-N 0.000 claims abstract description 87
- 150000001413 amino acids Chemical group 0.000 claims description 14
- 239000000203 mixture Substances 0.000 claims description 14
- 102000015626 Glucagon-Like Peptide-2 Receptor Human genes 0.000 claims description 11
- 108010024044 Glucagon-Like Peptide-2 Receptor Proteins 0.000 claims description 11
- 150000003839 salts Chemical class 0.000 claims description 8
- 150000001408 amides Chemical class 0.000 claims description 7
- 239000003814 drug Substances 0.000 claims description 6
- 229940121355 glucagon like peptide 2 (glp-2) analogues Drugs 0.000 claims description 6
- 150000002148 esters Chemical class 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- 102100040918 Pro-glucagon Human genes 0.000 abstract description 138
- DTHNMHAUYICORS-KTKZVXAJSA-N Glucagon-like peptide 1 Chemical class C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1N=CNC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 DTHNMHAUYICORS-KTKZVXAJSA-N 0.000 description 79
- 101800000224 Glucagon-like peptide 1 Proteins 0.000 description 68
- 208000006386 Bone Resorption Diseases 0.000 description 30
- 230000024279 bone resorption Effects 0.000 description 30
- 108010058003 Proglucagon Proteins 0.000 description 26
- 102000035554 Proglucagon Human genes 0.000 description 23
- 108010004460 Gastric Inhibitory Polypeptide Proteins 0.000 description 22
- 239000012634 fragment Substances 0.000 description 22
- 102100039994 Gastric inhibitory polypeptide Human genes 0.000 description 21
- 230000000694 effects Effects 0.000 description 21
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 19
- 150000001875 compounds Chemical class 0.000 description 18
- 201000010099 disease Diseases 0.000 description 18
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 18
- 230000011164 ossification Effects 0.000 description 18
- 108090000765 processed proteins & peptides Proteins 0.000 description 18
- 238000000034 method Methods 0.000 description 17
- 210000000988 bone and bone Anatomy 0.000 description 15
- 230000001965 increasing effect Effects 0.000 description 13
- 108090000623 proteins and genes Proteins 0.000 description 13
- 210000004369 blood Anatomy 0.000 description 12
- 239000008280 blood Substances 0.000 description 12
- 102000004169 proteins and genes Human genes 0.000 description 12
- 210000000936 intestine Anatomy 0.000 description 11
- GCYXWQUSHADNBF-AAEALURTSA-N preproglucagon 78-108 Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1N=CNC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 GCYXWQUSHADNBF-AAEALURTSA-N 0.000 description 11
- 208000001132 Osteoporosis Diseases 0.000 description 10
- 230000015572 biosynthetic process Effects 0.000 description 10
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 9
- 102000004877 Insulin Human genes 0.000 description 9
- 108090001061 Insulin Proteins 0.000 description 9
- 239000008103 glucose Substances 0.000 description 9
- 229940125396 insulin Drugs 0.000 description 9
- 230000009467 reduction Effects 0.000 description 9
- 210000002966 serum Anatomy 0.000 description 9
- 239000000556 agonist Substances 0.000 description 8
- 230000008416 bone turnover Effects 0.000 description 8
- 102000004196 processed proteins & peptides Human genes 0.000 description 8
- 229930091371 Fructose Natural products 0.000 description 7
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 description 7
- 239000005715 Fructose Substances 0.000 description 7
- 125000000539 amino acid group Chemical group 0.000 description 7
- 230000002060 circadian Effects 0.000 description 7
- 235000014113 dietary fatty acids Nutrition 0.000 description 7
- 229930195729 fatty acid Natural products 0.000 description 7
- 239000000194 fatty acid Substances 0.000 description 7
- 150000004665 fatty acids Chemical class 0.000 description 7
- 238000002347 injection Methods 0.000 description 7
- 239000007924 injection Substances 0.000 description 7
- 235000012054 meals Nutrition 0.000 description 7
- 235000015097 nutrients Nutrition 0.000 description 7
- 210000000496 pancreas Anatomy 0.000 description 7
- 238000003786 synthesis reaction Methods 0.000 description 7
- 238000012360 testing method Methods 0.000 description 7
- ODHCTXKNWHHXJC-VKHMYHEASA-N 5-oxo-L-proline Chemical group OC(=O)[C@@H]1CCC(=O)N1 ODHCTXKNWHHXJC-VKHMYHEASA-N 0.000 description 6
- 108060003199 Glucagon Proteins 0.000 description 6
- 241000282412 Homo Species 0.000 description 6
- 238000002474 experimental method Methods 0.000 description 6
- 230000002473 insulinotropic effect Effects 0.000 description 6
- 210000000963 osteoblast Anatomy 0.000 description 6
- 102000005962 receptors Human genes 0.000 description 6
- 108020003175 receptors Proteins 0.000 description 6
- 206010065687 Bone loss Diseases 0.000 description 5
- 102000051325 Glucagon Human genes 0.000 description 5
- 108091016366 Histone-lysine N-methyltransferase EHMT1 Proteins 0.000 description 5
- 102100035043 Histone-lysine N-methyltransferase EHMT1 Human genes 0.000 description 5
- 210000004027 cell Anatomy 0.000 description 5
- MASNOZXLGMXCHN-ZLPAWPGGSA-N glucagon Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O)C(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C1=CC=CC=C1 MASNOZXLGMXCHN-ZLPAWPGGSA-N 0.000 description 5
- 229960004666 glucagon Drugs 0.000 description 5
- 230000003914 insulin secretion Effects 0.000 description 5
- 150000004668 long chain fatty acids Chemical class 0.000 description 5
- 238000012545 processing Methods 0.000 description 5
- 238000005070 sampling Methods 0.000 description 5
- 230000019491 signal transduction Effects 0.000 description 5
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 4
- 206010017076 Fracture Diseases 0.000 description 4
- 102000007446 Glucagon-Like Peptide-1 Receptor Human genes 0.000 description 4
- 108010086246 Glucagon-Like Peptide-1 Receptor Proteins 0.000 description 4
- 101800004266 Glucagon-like peptide 1(7-37) Proteins 0.000 description 4
- 239000011575 calcium Substances 0.000 description 4
- 229910052791 calcium Inorganic materials 0.000 description 4
- 230000015556 catabolic process Effects 0.000 description 4
- 230000007423 decrease Effects 0.000 description 4
- 238000006731 degradation reaction Methods 0.000 description 4
- 206010012601 diabetes mellitus Diseases 0.000 description 4
- 210000001035 gastrointestinal tract Anatomy 0.000 description 4
- 108010063245 glucagon-like peptide 1 (7-36)amide Proteins 0.000 description 4
- JYGXADMDTFJGBT-VWUMJDOOSA-N hydrocortisone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 JYGXADMDTFJGBT-VWUMJDOOSA-N 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- URJOZSLMTIRWFW-QGZVFWFLSA-N (4r)-4-(1,3-benzodioxol-5-yl)-5,6-dimethoxy-4,9-dihydro-1h-benzo[f][2]benzofuran-3-one Chemical compound C1=C2OCOC2=CC([C@H]2C3=C(COC3=O)CC3=CC=C(C(=C32)OC)OC)=C1 URJOZSLMTIRWFW-QGZVFWFLSA-N 0.000 description 3
- 208000010392 Bone Fractures Diseases 0.000 description 3
- 108010022452 Collagen Type I Proteins 0.000 description 3
- 102000012422 Collagen Type I Human genes 0.000 description 3
- 102400000320 Glicentin Human genes 0.000 description 3
- 101800002945 Glicentin Proteins 0.000 description 3
- 101500028771 Homo sapiens Glucagon-like peptide 2 Proteins 0.000 description 3
- 101001039966 Homo sapiens Pro-glucagon Proteins 0.000 description 3
- LOJFGJZQOKTUBR-XAQOOIOESA-N NC(N)=NCCC[C@@H](C(O)=O)NC(=O)CNC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)CCC(O)=O)C)CC1=CN=CN1 Chemical group NC(N)=NCCC[C@@H](C(O)=O)NC(=O)CNC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)CCC(O)=O)C)CC1=CN=CN1 LOJFGJZQOKTUBR-XAQOOIOESA-N 0.000 description 3
- 208000010191 Osteitis Deformans Diseases 0.000 description 3
- 208000027868 Paget disease Diseases 0.000 description 3
- 108010033276 Peptide Fragments Proteins 0.000 description 3
- 102000007079 Peptide Fragments Human genes 0.000 description 3
- 230000003247 decreasing effect Effects 0.000 description 3
- 230000001419 dependent effect Effects 0.000 description 3
- 239000003163 gonadal steroid hormone Substances 0.000 description 3
- MGXWVYUBJRZYPE-YUGYIWNOSA-N incretin Chemical class C([C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCC(N)=O)C(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1C=CC(O)=CC=1)[C@@H](C)O)[C@@H](C)CC)C1=CC=C(O)C=C1 MGXWVYUBJRZYPE-YUGYIWNOSA-N 0.000 description 3
- 239000000859 incretin Substances 0.000 description 3
- 210000004347 intestinal mucosa Anatomy 0.000 description 3
- 208000027202 mammary Paget disease Diseases 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 210000002997 osteoclast Anatomy 0.000 description 3
- 208000009137 Behcet syndrome Diseases 0.000 description 2
- 102000003688 G-Protein-Coupled Receptors Human genes 0.000 description 2
- 108090000045 G-Protein-Coupled Receptors Proteins 0.000 description 2
- 206010020584 Hypercalcaemia of malignancy Diseases 0.000 description 2
- 206010027476 Metastases Diseases 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- 208000003076 Osteolysis Diseases 0.000 description 2
- 229930003316 Vitamin D Natural products 0.000 description 2
- QYSXJUFSXHHAJI-XFEUOLMDSA-N Vitamin D3 Natural products C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C/C=C1\C[C@@H](O)CCC1=C QYSXJUFSXHHAJI-XFEUOLMDSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 230000033228 biological regulation Effects 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- -1 carboxylate salts Chemical class 0.000 description 2
- 230000001413 cellular effect Effects 0.000 description 2
- 238000007385 chemical modification Methods 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 229940096422 collagen type i Drugs 0.000 description 2
- 230000001332 colony forming effect Effects 0.000 description 2
- 230000007812 deficiency Effects 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 230000018109 developmental process Effects 0.000 description 2
- 235000018823 dietary intake Nutrition 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000000262 estrogen Substances 0.000 description 2
- 230000007717 exclusion Effects 0.000 description 2
- 201000010934 exostosis Diseases 0.000 description 2
- 230000006870 function Effects 0.000 description 2
- UKVFVQPAANCXIL-FJVFSOETSA-N glp-1 (1-37) amide Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 UKVFVQPAANCXIL-FJVFSOETSA-N 0.000 description 2
- 229940088597 hormone Drugs 0.000 description 2
- 239000005556 hormone Substances 0.000 description 2
- 208000008750 humoral hypercalcemia of malignancy Diseases 0.000 description 2
- 229960000890 hydrocortisone Drugs 0.000 description 2
- 201000010930 hyperostosis Diseases 0.000 description 2
- 239000000411 inducer Substances 0.000 description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 description 2
- 230000000968 intestinal effect Effects 0.000 description 2
- 210000004153 islets of langerhan Anatomy 0.000 description 2
- 208000029791 lytic metastatic bone lesion Diseases 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 208000030159 metabolic disease Diseases 0.000 description 2
- 230000009401 metastasis Effects 0.000 description 2
- 239000011707 mineral Substances 0.000 description 2
- 230000030991 negative regulation of bone resorption Effects 0.000 description 2
- 238000007410 oral glucose tolerance test Methods 0.000 description 2
- 230000001599 osteoclastic effect Effects 0.000 description 2
- 208000005368 osteomalacia Diseases 0.000 description 2
- 208000002865 osteopetrosis Diseases 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 230000001737 promoting effect Effects 0.000 description 2
- 238000011321 prophylaxis Methods 0.000 description 2
- 229940044601 receptor agonist Drugs 0.000 description 2
- 239000000018 receptor agonist Substances 0.000 description 2
- 230000002829 reductive effect Effects 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 206010039073 rheumatoid arthritis Diseases 0.000 description 2
- 230000028327 secretion Effects 0.000 description 2
- 230000004936 stimulating effect Effects 0.000 description 2
- 230000000638 stimulation Effects 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 239000011710 vitamin D Substances 0.000 description 2
- 235000019166 vitamin D Nutrition 0.000 description 2
- 150000003710 vitamin D derivatives Chemical class 0.000 description 2
- 229940046008 vitamin d Drugs 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- NGJOFQZEYQGZMB-KTKZVXAJSA-N (4S)-5-[[2-[[(2S,3R)-1-[[(2S)-1-[[(2S,3R)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[2-[[(2S)-5-amino-1-[[(2S)-1-[[(2S)-1-[[(2S)-6-amino-1-[[(2S)-1-[[(2S)-1-[[(2S,3S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-6-amino-1-[[2-[[(1S)-4-carbamimidamido-1-carboxybutyl]amino]-2-oxoethyl]amino]-1-oxohexan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-1-oxopropan-2-yl]amino]-3-methyl-1-oxopentan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-4-carboxy-1-oxobutan-2-yl]amino]-1-oxohexan-2-yl]amino]-1-oxopropan-2-yl]amino]-1-oxopropan-2-yl]amino]-1,5-dioxopentan-2-yl]amino]-2-oxoethyl]amino]-4-carboxy-1-oxobutan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]-3-carboxy-1-oxopropan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-3-hydroxy-1-oxobutan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-3-hydroxy-1-oxobutan-2-yl]amino]-2-oxoethyl]amino]-4-[[(2S)-2-[[(2S)-2-amino-3-(1H-imidazol-4-yl)propanoyl]amino]propanoyl]amino]-5-oxopentanoic acid Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 NGJOFQZEYQGZMB-KTKZVXAJSA-N 0.000 description 1
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 1
- VOUAQYXWVJDEQY-QENPJCQMSA-N 33017-11-7 Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](C(C)C)C(=O)NCC(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)NCC(=O)NCC(=O)N1CCC[C@H]1C(=O)NCC(=O)N[C@@H](C)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N1[C@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O)CCC1 VOUAQYXWVJDEQY-QENPJCQMSA-N 0.000 description 1
- HFDKKNHCYWNNNQ-YOGANYHLSA-N 75976-10-2 Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(N)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](C)NC(=O)[C@H](CCSC)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H]1N(CCC1)C(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@@H](NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](C)N)C(C)C)[C@@H](C)O)C1=CC=C(O)C=C1 HFDKKNHCYWNNNQ-YOGANYHLSA-N 0.000 description 1
- 208000020084 Bone disease Diseases 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- 108010075254 C-Peptide Proteins 0.000 description 1
- 235000005979 Citrus limon Nutrition 0.000 description 1
- 244000131522 Citrus pyriformis Species 0.000 description 1
- 108020004705 Codon Proteins 0.000 description 1
- 108010035532 Collagen Proteins 0.000 description 1
- 102000008186 Collagen Human genes 0.000 description 1
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 description 1
- 229940080349 GPR agonist Drugs 0.000 description 1
- 108010088406 Glucagon-Like Peptides Proteins 0.000 description 1
- 229940089838 Glucagon-like peptide 1 receptor agonist Drugs 0.000 description 1
- 101800004295 Glucagon-like peptide 1(7-36) Proteins 0.000 description 1
- 229920002527 Glycogen Polymers 0.000 description 1
- 102000004457 Granulocyte-Macrophage Colony-Stimulating Factor Human genes 0.000 description 1
- 108010017213 Granulocyte-Macrophage Colony-Stimulating Factor Proteins 0.000 description 1
- 206010020100 Hip fracture Diseases 0.000 description 1
- 206010020707 Hyperparathyroidism primary Diseases 0.000 description 1
- 102000003746 Insulin Receptor Human genes 0.000 description 1
- 108010001127 Insulin Receptor Proteins 0.000 description 1
- 102000004889 Interleukin-6 Human genes 0.000 description 1
- 108090001005 Interleukin-6 Proteins 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 208000034578 Multiple myelomas Diseases 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 240000008790 Musa x paradisiaca Species 0.000 description 1
- 235000018290 Musa x paradisiaca Nutrition 0.000 description 1
- 241000700124 Octodon degus Species 0.000 description 1
- 206010030247 Oestrogen deficiency Diseases 0.000 description 1
- 102000004067 Osteocalcin Human genes 0.000 description 1
- 108090000573 Osteocalcin Proteins 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 102000018886 Pancreatic Polypeptide Human genes 0.000 description 1
- 102000035195 Peptidases Human genes 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- 206010035226 Plasma cell myeloma Diseases 0.000 description 1
- 201000000981 Primary Hyperparathyroidism Diseases 0.000 description 1
- RJKFOVLPORLFTN-LEKSSAKUSA-N Progesterone Chemical class C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)C)[C@@]1(C)CC2 RJKFOVLPORLFTN-LEKSSAKUSA-N 0.000 description 1
- 101500026175 Rattus norvegicus Glucagon-like peptide 2 Proteins 0.000 description 1
- 241000283984 Rodentia Species 0.000 description 1
- 206010049416 Short-bowel syndrome Diseases 0.000 description 1
- 101000983124 Sus scrofa Pancreatic prohormone precursor Proteins 0.000 description 1
- 208000025865 Ulcer Diseases 0.000 description 1
- 241000251539 Vertebrata <Metazoa> Species 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 230000008649 adaptation response Effects 0.000 description 1
- 210000001789 adipocyte Anatomy 0.000 description 1
- 210000000577 adipose tissue Anatomy 0.000 description 1
- OGSPWJRAVKPPFI-UHFFFAOYSA-M alendronate(1-) Chemical compound NCCCC(O)(P(O)(O)=O)P(O)([O-])=O OGSPWJRAVKPPFI-UHFFFAOYSA-M 0.000 description 1
- 125000005907 alkyl ester group Chemical group 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 239000003263 anabolic agent Substances 0.000 description 1
- 230000001195 anabolic effect Effects 0.000 description 1
- 229940094957 androgens and estrogen Drugs 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 210000002449 bone cell Anatomy 0.000 description 1
- 230000008468 bone growth Effects 0.000 description 1
- 230000004097 bone metabolism Effects 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 235000014121 butter Nutrition 0.000 description 1
- BBBFJLBPOGFECG-VJVYQDLKSA-N calcitonin Chemical compound N([C@H](C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N1[C@@H](CCC1)C(N)=O)C(C)C)C(=O)[C@@H]1CSSC[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1 BBBFJLBPOGFECG-VJVYQDLKSA-N 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 230000001925 catabolic effect Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 235000013351 cheese Nutrition 0.000 description 1
- 210000001612 chondrocyte Anatomy 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 229920001436 collagen Polymers 0.000 description 1
- 210000001072 colon Anatomy 0.000 description 1
- 230000001609 comparable effect Effects 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 238000012937 correction Methods 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000000378 dietary effect Effects 0.000 description 1
- 230000003292 diminished effect Effects 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 230000008508 epithelial proliferation Effects 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 235000019197 fats Nutrition 0.000 description 1
- 210000002950 fibroblast Anatomy 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 235000011389 fruit/vegetable juice Nutrition 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 230000005176 gastrointestinal motility Effects 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 239000003877 glucagon like peptide 1 receptor agonist Substances 0.000 description 1
- 230000004190 glucose uptake Effects 0.000 description 1
- 229940096919 glycogen Drugs 0.000 description 1
- 239000003102 growth factor Substances 0.000 description 1
- 230000003054 hormonal effect Effects 0.000 description 1
- 238000002657 hormone replacement therapy Methods 0.000 description 1
- 210000003405 ileum Anatomy 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 230000006362 insulin response pathway Effects 0.000 description 1
- 229940100601 interleukin-6 Drugs 0.000 description 1
- 230000017306 interleukin-6 production Effects 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 235000015094 jam Nutrition 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 244000144972 livestock Species 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 210000004379 membrane Anatomy 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 230000009245 menopause Effects 0.000 description 1
- 108020004999 messenger RNA Proteins 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 210000000663 muscle cell Anatomy 0.000 description 1
- 239000002773 nucleotide Substances 0.000 description 1
- 125000003729 nucleotide group Chemical group 0.000 description 1
- 235000016709 nutrition Nutrition 0.000 description 1
- 235000015205 orange juice Nutrition 0.000 description 1
- 230000004768 organ dysfunction Effects 0.000 description 1
- 230000001009 osteoporotic effect Effects 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 230000037081 physical activity Effects 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 230000029537 positive regulation of insulin secretion Effects 0.000 description 1
- 208000001685 postmenopausal osteoporosis Diseases 0.000 description 1
- 230000001323 posttranslational effect Effects 0.000 description 1
- 230000036515 potency Effects 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 239000000583 progesterone congener Substances 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 235000019833 protease Nutrition 0.000 description 1
- 230000006337 proteolytic cleavage Effects 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 235000012780 rye bread Nutrition 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 230000003248 secreting effect Effects 0.000 description 1
- 230000009645 skeletal growth Effects 0.000 description 1
- 210000002027 skeletal muscle Anatomy 0.000 description 1
- 210000000813 small intestine Anatomy 0.000 description 1
- 206010041569 spinal fracture Diseases 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 238000013519 translation Methods 0.000 description 1
- 230000032258 transport Effects 0.000 description 1
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 1
- 230000001228 trophic effect Effects 0.000 description 1
- 230000036269 ulceration Effects 0.000 description 1
- 238000011144 upstream manufacturing Methods 0.000 description 1
- 230000036325 urinary excretion Effects 0.000 description 1
- 235000013618 yogurt Nutrition 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/22—Hormones
- A61K38/27—Growth hormone [GH], i.e. somatotropin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/22—Hormones
- A61K38/26—Glucagons
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/22—Hormones
- A61K38/30—Insulin-like growth factors, i.e. somatomedins, e.g. IGF-1, IGF-2
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/02—Nutrients, e.g. vitamins, minerals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/14—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/18—Drugs for disorders of the endocrine system of the parathyroid hormones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
Definitions
- This invention relates to the use of glucagon-like peptide-1 (GLP-1) as well as inducers, analogues and derivatives of GLP-1, and of glucagon-like peptide-2(GLP-2) and inducers analogues and derivatives of GLP-2, in methods and compositions, in particular pharmaceutical formulations, for the treatment of diseases wherein bone resorption and/or insufficient bone formation is a factor, such as osteoporosis.
- GLP-1 glucagon-like peptide-1
- inducers analogues and derivatives of GLP-1
- GLP-2 glucagon-like peptide-2
- inducers analogues and derivatives of GLP-2 in methods and compositions, in particular pharmaceutical formulations, for the treatment of diseases wherein bone resorption and/or insufficient bone formation is a factor, such as osteoporosis.
- Glucagon-like peptide-1 (GLP-1) and glucagon-like peptide-2 (GLP-2) are fragments of the proglucagon molecule and the proglucagon molecule has a sequence of 160 amino acids.
- Proglucagon originates from preproglucagon which is synthesised in the L-cells in the distal ileum, in the pancreas and in the brain. Processing of preproglucagon to give GLP-1 and GLP-2 occurs mainly in the L-cells.
- the amino acid sequence of the proglucagon fragment 72-117 is given i. e. by Bell, G. I. et al. (Nature 304 368-371 (1983 )).
- the proglucagon fragment 78-108 is commonly referred to as GLP-1 (7-37). In analogy with this, the proglucagon fragment 72-108 is in the present text also referred to as GLP-1 (37) .
- GLP-1 The proglucagon fragment of GLP-1 (7-36) amide is the naturally occurring form in humans and is usually referred to as GLP-1.
- Gly8-GLP1 (7-37) designates a fragment of GLP-1 formally derived from GLP-1 by replacing the amino acid residue in position 8 (Ala) by Gly.
- GLP-1 (7-37) and analogues thereof have been disclosed, for example,Gln9-GLP-1 (7-37),D-Gln9-GLP-1 (7-37), acetyl-Lys9-GLP-1 (7-37),Thrl6-Lysl8-GLP-1 (7-37), Lys18-GLP1 (7-37) and the like, and derivatives thereof including, for example, acid addition salts, carboxylate salts, lower alkyl esters, and amides (see e. g. WO 91/11457 ).
- GLP-1 Glucagon-like peptide-1
- GLP-1 is known to stimulate insulin secretion and inhibit glucagon secretion and thereby lowers blood glucose, Andreasen, J. J. et al. (Digestion55 221-228 (1994 )).
- the various disclosed forms of GLP-1 are known to stimulate insulin secretion and cAMP formation (see e. g., Mojsov, S. (Int. J. Peptide Protein Research 40 333343 (1992 ))).
- Glucagon-like peptide-2(GLP-2) is a 33 amino acid peptide fragment of proglucagon corresponding to the sequence of the proglucagon fragment 126-158.
- GLP-2 shows remarkable homology in terms of amino acid sequence to glucagon and glucagon-like peptide-1 (GLP-1).
- GLP-1 glucagon and glucagon-like peptide-1
- different mammalian forms of GLP-2 are highly conserved.
- the human GLP-2 (hGLP-2) and the degu (a south American rodent) GLP-2 differ from rat GLP-2(rGLP-2) by one and three amino acids respectively.
- GLP-2 Various vertebrate forms of GLP-2 have been reported by many authors including Buhl et al., J. Biol. Chem., 1988, 263 (18): 8621 , Nishi and Steiner, Mol. Endocrinol.,, 1990, 4: 1192-8 , and Irwin and Wong, Mol. Endocrinol., 1995, 9 (3): 267-77 . The sequences reported by these authors are incorporated by reference.
- GLP-2 When given exogenously, GLP-2 can produce a marked increase in the proliferation of small intestinal epithelium of the test mice, apparently with no undesirable side effects ( Drucker et al., 1996, PNAS: USA, 93 7911-7916 ). Moreover, GLP-2 has also been shown to increase D-glucose maximal transport rate across the intestinal basolateral membrane ( Cheeseman and Tseng, 1996, American Journal of Physiology 271G477-G482 ).
- Osteoporosis is the most common bone disease in humans. It is a serious and frequent disease, which occurs worldwide.
- osteoporosis The single most important risk factor for osteoporosis is oestrogen deficiency, and it is estimated that up to one third of postmenopausal women will be affected if left untreated, Schlemmer, A. et al., Eur. J. Endocrinol. 140: 332-337 (1999 ).
- a primary event leading to osteoporotic bone loss is the increase in bone turnover associated with menopause.
- the acute increase in bone resorption seen with the decline in endogenous oestrogen production is followed by a coupled, but less accentuated increase in bone formation.
- Other diseases and metabolic disorders which result in loss of bone structure are for instance, hyperparathyroidism, Paget's disease, hypercalcemia of malignancy, osteolytic lesions produced by bone metastasis, bone loss due to immobilisation or sex hormone deficiency, Behcet's disease, osteomalacia, hyperostosis and osteopetrosis.
- GLP-1 peptide or GLP-2 peptide have an effect on loss of bone mass and/or insufficient bone formation in humans. Based on these observations it is now possible to provide a medicament and a method for the prophylaxis or treatment of diseases or disorders wherein bone resorption and/or insufficient bone formation is a factor, such as osteoporosis.
- the present invention relates to the use of a composition comprising a glucagon-like peptide-1 (GLP-1) or an analogue or derivative thereof, and/or a glucagon-like peptide-2 (GLP-2) or an analogue or derivative thereof, to inhibit bone resorption and/or to promote bone formation.
- GLP-1 glucagon-like peptide-1
- GLP-2 glucagon-like peptide-2
- an analogue is used to designate a peptide wherein one or more amino acid residues of the parent peptide have been substituted by another amino acid residue and/or wherein one or more amino acid residues of the parent peptide have been deleted and/or wherein one or more amino acid residues have been added to the parent peptide.
- analogue'further includes mimetics so the said peptides which bind to the receptors for said peptides and activate said receptor to produce an output messenger or signal equivalent in kind to that produced upon binding of GLP-1 or GLP-2 respectively.
- Such analogues may be adapted to resist degradation in the body to an extent greater than GLP-1 or GLP-2 and so may have a longer half life or may be orally administerable.
- Such analogues will include pseudopeptides modelled on GLP-1 or GLP-2 in which one or more amino acid residues have been substituted with structurally similar but peptidase resistant amino acid mimicking moieties.
- thedesignation"amino acid residue designates the residue of an amino acid which can be coded for by the genetic code, via a triplet ("codon') of nucleotides.
- the peptides to which the invention relates are referred to collectivelyas"GLP-1 peptides"and similarly collectively as"GLP-2 peptides'.
- 'Derivatives'referred to herein include for example, acid addition salts, carboxylate salts, lower alkyl(e. g. Ci-Cg, more preferablyCl-C3, esters and amides. Also included are substances formed by chemical modification of GLP-2 peptide which retain the bone resorption decreasing and/or bone formation increasing properties of GLP-2 at an equivalent or increased level.
- the present invention relates to the use of a composition comprising a glucagon-like peptide-1 (GLP-1) or an analogue or derivative thereof, and/or a glucagon-like peptide-2 (GLP-2) or an analogue or derivative thereof, in the preparation of a medicament for the treatment of a disease wherein bone resorption and/or insufficient bone formation is a factor.
- GLP-1 glucagon-like peptide-1
- GLP-2 glucagon-like peptide-2
- the disease is osteoporosis.
- the present invention relates to a method of inhibiting bone resorption and/or promoting bone formation, comprising, administering to a subject a compound selected from the group consisting of GLP-1, GLP-2, GLP-1 analogues, GLP-2 analogues,GLP-1 derivatives, GLP-2 derivatives, agonists of the GLP-1 or the GLP-2 receptor, agonists of the GLP-1 or the GLP-2 signal transduction cascade, compounds that stimulate synthesis of endogenous GLP-1 or GLP-2, compounds that stimulate release of endogenous GLP-1 or GLP-2, and pharmaceutically acceptable derivatives such as esters, amides or salts thereof.
- a preferred embodiment of the present invention relates to a method wherein the composition is selected from the group consisting of GLP-2, GLP-2 analogues, GLP-2 derivatives, and pharmaceutically acceptable salts, esters or amides thereof.
- the present invention relates to a method wherein the composition is administered orally.
- Another aspect of the present invention relates to a method of prophylactically treating a subject at risk of developing a disease wherein bone resorption and/or insufficient bone formation is a factor, the method comprising the steps of a) identifying a subject at risk of developing such a disease; and b) administering to the subject an amount of a compound selected from the group consisting of GLP-1, GLP-2, GLP 1 analogues, GLP-2 analogues, GLP-1 derivatives, GLP-2 derivatives, agonists of the GLP-1 or theGLP-2 receptor, agonists of the GLP-1 or the GLP-2 signal transduction cascade, compounds that stimulate synthesis of endogenous GLP-1 or GLP-2, compounds that stimulate release of endogenous GLP-1 or GLP-2, and pharma ceutically acceptable salts, amides or esters thereof, effective to inhibit onset of said disease.
- the present invention relates to a method of treatment wherein the disease is osteoporosis.
- the present invention relates to a method wherein the subject is a human.
- compositions used for inhibition of bone resorption and/or the promotion of bone formation comprising a compound selected from the group consisting of GLP-1, GLP-2,
- GLP-1 analogues GLP-2 analogues, GLP-1 derivatives, GLP-2 derivatives, agonists of the GLP-1 or the GLP-2 receptor, agonists of the GLP-1 or the GLP-2 signal transduction cascade, compounds that stimulate synthesis of endogenous GLP-1 or GLP-2, compounds that stimulate release of endogenous GLP-1 or GLP-2, and pharmaceutically acceptable salts thereof.
- the compound is an orally effective analogue or derivative.
- a compound is on which stimulates endogenous production or release of GLP-1 or GLP2, it is not nutritionally effective or is not found as a component of foodstuffs.
- the present invention relates to a pharmaceutical composition for use in the therapeutic or prophylactic treatment of a disease wherein bone resorption or insufficient bone formation is a factor, said composition comprising a compound selected from the group consisting of GLP-1, GLP-2, GLP-1 analogues, GLP-2 analogues, GLP-1 derivatives, GLP-2 derivatives, agonists of the GLP-1 or the GLP-2 receptor, agonists of the GLP-1 or the GLP-2 signal transduction cascade, compounds that stimulate synthesis of endogenous GLP-1 or GLP-2, compounds that stimulate release of endogenous GLP-1 or GLP2, and pharmaceutically acceptable salts thereof.
- This invention comprises the use of glucagon-like peptide-1 (GLP-1), analogues and derivatives of GLP-1, glucagon-like peptide-2 (GLP-2), analogues and derivatives of GLP-2, for the treatment of diseases wherein bone resorption and/or insufficient bone formation is a factor, such as osteoporosis.
- GLP-1 glucagon-like peptide-1
- GLP-2 glucagon-like peptide-2
- analogues and derivatives of GLP-2 for the treatment of diseases wherein bone resorption and/or insufficient bone formation is a factor, such as osteoporosis.
- biochemical markers it is well known to use biochemical markers to be able to biochemically assess the level of bone resorption and formation in order to evaluate a risk for a future fracture.
- the skeleton is (among other things) a reservoir of nutrients, including minerals such as calcium and phosphate.
- This reservoir is usually well protected but in situations of insufficient access to nutrients giving rise to a decreasing extra cellular concentration of these nutrients the stores of these in the skeleton can be mobilised. Likewise, in situations of sufficient access to nutrients the metabolic machinery of the body is set to preserve the stores.
- Such mobilisation of the stores can be achieved by stimulating osteoclastic bone resorption, and likewise resorption can be decreased when dietary availability of nutrients increases.
- the nutrients that can inhibit bone resorption may be a sugar, a protein, or a fatty acid, or a triglyceride, or a mineral.
- Fatty acids used were preferably long chain fatty acids.
- the fragments of proglucagon produced in the intestine have a role in the inhibition of bone resorption and also a role in promoting bone formation (an anabolic bone effect).
- the proglucagon expressed in the a-cells of the endocrine pancreas and in the enteroendocrine L-cells of the intestine arises from the transcription of a single gene and the translation of identical mRNAs in these two tissues.
- Biologic diversity in the expression of the proglucagon gene occurs at the level of a remarkably tissue-specific alternative post-translational processing, resulting in the formation of the bioactive peptide glucagon in the pancreas and the reciprocal insulin-stimulating GLP-1 in the intestine.
- glucagon and GLP sequences in intestine and pancreas, respectively, are retained as unprocessed proglucagon fragments: enteroglucagon (glicentin) in the intestine and the major proglucagon fragment in the pancreas, Habener, J. F., Diabetes Mellitus 68-78 (1996 ).
- Glicentin or proglucagon fragment 1-69 is cleaved in the pancreas to GRPP (glicentin-related pancreatic polypeptide) and glucagon, whereas the major proglucagon fragment 72-158 is cleaved (processed) in the intestine to GLP-1 (proglucagon fragment 78-107) and GLP-2 (proglucagon fragment 126-158) fragments.
- GRPP glicentin-related pancreatic polypeptide
- proglucagon fragment 72-158 is cleaved (processed) in the intestine to GLP-1 (proglucagon fragment 78-107) and GLP-2 (proglucagon fragment 126-158) fragments.
- GLP-1 of the intestine is an anabolic hormone that among other things facilitates stimulation of insulin secretion and glucose uptake during feeding, whereas glucagon from pancreas is the most important catabolic hormone that acts during periods of fasting to break down glycogen (and thereby to increase glucose output by the liver), skeletal muscle, and adipose tissue.
- the proteolytic cleavage of the proglucagon in the intestine is part of a complicated process.
- At least four peptides of GLP-1 result from the processing : two peptides of 37 and 36 amino acids, GLP-1 (1-37) and GLP-1 (1-36) amide; and two aminoterminally truncated isopeptides, GLP-1 (7-37) and GLP1 (7-36) amide.
- GLP-1 1-37
- GLP-1 (1-36) amide two aminoterminally truncated isopeptides
- GLP-1 (7-37) and GLP1 (7-36) amide Only the two truncated GLP-ls have insulinotropic activities. Previously, no biologic activities have been found for either of the aminoterminally extended forms ofGLP-1.
- GLP-1 has been proven to be a potent glucose-dependent insulinotropic peptide distinct from GIP.
- GIP Gastric Inhibitory Polypeptide which has been changed to Glucosedependent Insulinotropic Polypeptide
- GIP is an incretin that stimulates insulin secretion directly in a glucose-dependent manner.
- proglucagon 126-158 The intestinal processing of proglucagon also gives rise to GLP-2 corresponding to proglucagon 126-158. Only a single form is known in humans, Hartmann B et al., Peptides 2000;21 (1) : 73-80 .
- GLP-2 seems to share some of the effect of GLP-1 on gastrointestinal motility and secretion, Wojdemann, M. et al., J Clin Endocrinol Metab 1999; 84 (7): 2513-2517 and Wo demann, M. et al, Scand J Gastroenterol 1998; 33 (8): 828-832 , but has no direct effect on the pancreatic islets.
- GLP-2 has trophic effect on the intestinal mucosa, and may act physiologically as a growth factor involved in adaptive responses of the gut to surgery or nutritional variation, Drucker, D. J. et al., Proc Natl Acad Sci USA 1996; 93 (15): 7911-7916 and Thulesen, J.
- GLP-1 peptides Compounds which can be useful as GLP-1 peptides according to the present invention are described in International Patent Application No. WO 87/06941 which relates to a peptide fragment which comprises GLP-1 (7-37) and functional derivatives thereof and to its use as an insulinotropic agent.
- GLP-1 analogues are described in International Patent Application No. WO 90/11296 which relates to peptide fragments which comprise GLP-1 (7-36) and functional derivatives thereof and have an insulinotropic activity which exceeds the insulinotropic activity of GLP-1 (1-36) or GLP-1 (1-37) and to their use as insulinotropic agents.
- Derivatives of naturally-occurring GLP-1 molecules are those peptides which are obtained by fragmenting a naturallyoccurring sequence, or are synthesised based upon a knowledge of the sequence of the naturally-occurring amino acid sequence of the genetic material (DNA or RNA) which encodes this sequence.
- the term "derivatives” also includes chemical modification of natural or unnatural GLP-1 or GLP-2 molecules. Processes for preparing these derivatives are well known to organic and peptide chemists of ordinary skill (see, e. g. WO 91/11457 ).
- GLP-1 receptor agonist and "GLP-2 receptor agonist”mean any molecule which on binding to the GLP-1 receptor, respectively the GLP-2 receptor result in activation of the GLP-1 receptor, respectively the GLP-2 receptor, and include for example GLP-1, GLP-2 or peptidic analogues of GLP-1 and GLP-2.
- GLP-1 receptor and the GLP-2 receptor are G-protein coupled receptors.
- methods commonly used in this field to identify G-protein coupled receptor agonists may be useful applied to the GLP-1 receptor respectively the GLP-2 receptor.
- One useful methodology for assessing compounds for GLP-2 receptor agonist activity is disclosed in US Patent No. 6077949 .
- GLP-1 and of GLP-2 are not yet fully elucidated. It may be that one or both operates through a signal transduction cascade in which there may be active constituents either upstream or downstream or both from the GLP peptide. According to the invention, it is permissible to intervene at any point in such a cascade to produce a reduction in the rate of bone resorption and/or to promote the rate of bone formation by the mechanism of the cascade. This may involve stimulating the synthesis or release of endogenous GLP peptide or administering or triggering endogenous synthesis or release of another compound active in the cascade downstream from the GLPpeptide, e. g. one produced in response to the GLP peptide binding to a receptor.
- Osteoblasts are of mesenchymal origin derived from fibroblast colony forming units, as are chondrocytes, muscle cells and adipocytes. Osteoblasts are capable of secreting a number of factors (such as interleukins-6 and11 ; MCS-F and GM-CSF) that can affect the development of osteoclasts. Osteoclasts develop fromgranulocye-macrophage colony forming units and their development is modulated by a variety of factors, including interleukins1, 3, 6 and11.
- interleukin-6 because its production from osteoblasts is stimulated by PTH and vitamin D and because of its possible involvement in several diseases including primaryhyperparathyroidism, multiple myeloma, rheumatoid arthritis, Paget's disease and hypogonadal osteoprosis.
- Interleukin-6 production from osteoblasts is regulated by sex-hormones (androgens and estrogens) which act on theIl-6 promotor.
- the role ofIl-6 (in contrast toIl-11) in normal osteoclastic function is unclear but in certain pathologic states theIl-6 receptor is upregulated andIl-6 may then exert is effect.
- gpl30 andI1-6mRNA are all increased compared to normal cells.
- I1-6 plays an important role in the accelerated bone loss associated with postmenopausal osteoporosis.
- GLP-1 and GLP-2 may play an important role in the regulation of both skeletal growth in the child, and skeletal remodelling in the adult.
- GLP may act on receptors present in bone derived cells and stimulation of these cells with GLP leads to an increase in intracellular calcium concentration and cellular cAMP content, resulting in increased type I collagen synthesis and inhibition of PTHstimulated bone resorption.
- the invention includes the use of other fragments obtainable from the cleavage of the major proglucagon fragment which also haveGLP-like activity.
- subject includes a human or other mammal and including livestock and pets.
- Administration may be via any route known to be effective by the physician of ordinary skill.
- Parenteral administration may be performed by subcutaneous, intramuscular, intraperitoneal or intravenous injection of a dosage form into the body by means of a sterile syringe, optionally a pen-like syringe or some other mechanical device such as an infusion pump.
- a further option is a composition which may be a powder or a liquid for the administration in the form of a nasal or pulmonary spray.
- the administration may betransdermally, e. g. from a patch.
- compositions suitable for oral, buccal, rectal and vaginal administration may also be provided.
- the oral route of administration is preferred for compounds used in the present invention which are orally effective.
- Serum FSH was measured by IRMA(Coat-A-Count@/DPC/Los Angeles CA).
- Serum C-telopeptide fragments of collagen type I degradation (S-CTX) were measured byELISA, serum CrossLapsTM assay (Osteometer BioTech A/S-Denmark).
- Serum osteocalcin was determined byELISA, an assay which determines the Nterminal mid segment of the molecule.
- Serum insulin and cpeptide were both assessed by RIA (Coat-A-Counts for insulin and Double Antibody C-peptide for c-peptide bothDPC, Los Angeles, CA).
- Oral fructose consisted of 75 g fructose dissolved in 300 ml water with juice of a half lemon added.
- Oral fructose induced a reduction of 36 % in S-CTX after 2 hours ( Figure 1A ) whereas the occurrence of GLP-1 was doubled to the level of 220 % after 2 hours compared to the baseline of 100 % at To.
- the fragment of GLP-1 is one fragment of the major proglucagon fragment which is cleaved and activated in the intestine. According, the occurrence of the other parts or fragments are doubled to a similar level as GLP-1 and therefore can take part in the association of the reduction in S-CTX.
- the level of GIP was almost maintained at the baseline.
- Oral long chained fatty acids consisted of 70 ml emulsion of long chained fatty acids (Calogen).
- Oral protein consisted of 40 g protein powder (Casilan) dissolved in 600 ml water.
- Oral protein induced a reduction of 45% in S-CTX after 2 hours ( Figure 1C ) whereas the occurrence of GLP-2 and GIP were both increased.
- the level of GIP was increased from 8 pM to 17 pM and the occurrence of GLP-2 was increased from 36 pM to 57 pM after 1 hour decrease slightly after 2 hours to the level of 51 pM.
- peripheral venous blood was collected 15 minute before the test meal and 10,20, 30,45,60,120 and 180 minutes after the start of the meal, which was completed in 15 minutes.
- the normal mixed meal consisted of rye bread, toast, butter, cheese, jam, yoghurt, banana, and orange juice (total weight 755g), with an energy content of 3.92 MJ and a protein: carbohydrate: fat energy ratio of 10%: 52%: 37% evaluated from food tables.
- a normal mixed meal induced a reduction of 40% in S-CTX after 2 hours ( Figure 2 ) whereas the occurrence of GLP-1 and GLP-2 were both increased.
- the level of GLP-1 was increased from 70 pM to 98 pM after 3 hours and the occurrence of GLP-2 was increased from 10 pM to 22 pM after 3 hours.
- Blood samples were drawn at regular intervals before, during, and after the injection.
- test persons received a subcutaneous bolus injection of 400 Ag synthetic human GLP-2.
- the GLP-2 injection induced a reduction of 33% in S-CTX after 3 hours whereas the level of GLP-2 increased naturally after the injection to a peak after 1 hour indicating the association between GLP-2 and the reduction in S-CTX.
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Diabetes (AREA)
- Endocrinology (AREA)
- Immunology (AREA)
- Physical Education & Sports Medicine (AREA)
- Epidemiology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Gastroenterology & Hepatology (AREA)
- Zoology (AREA)
- Rheumatology (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Molecular Biology (AREA)
- Nutrition Science (AREA)
- Pain & Pain Management (AREA)
- Emergency Medicine (AREA)
- Child & Adolescent Psychology (AREA)
- Pulmonology (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB0022844A GB0022844D0 (en) | 2000-09-18 | 2000-09-18 | Use of GLP-1 and GLP-2 peptides |
GB0029920A GB0029920D0 (en) | 2000-12-07 | 2000-12-07 | Use of glp-1 and glp-2 peptides |
EP01982302A EP1326630B1 (fr) | 2000-09-18 | 2001-09-17 | Utilisation de peptides glp-2 |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP01982302A Division EP1326630B1 (fr) | 2000-09-18 | 2001-09-17 | Utilisation de peptides glp-2 |
Publications (1)
Publication Number | Publication Date |
---|---|
EP1970072A1 true EP1970072A1 (fr) | 2008-09-17 |
Family
ID=26245018
Family Applications (3)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP01982302A Expired - Lifetime EP1326630B1 (fr) | 2000-09-18 | 2001-09-17 | Utilisation de peptides glp-2 |
EP08156283A Withdrawn EP1970072A1 (fr) | 2000-09-18 | 2001-09-17 | Utilisation de peptides GLP-2 pour le traitement d'hyperparathyroïdie |
EP01967517A Expired - Lifetime EP1414486B1 (fr) | 2000-09-18 | 2001-09-18 | Utilisation de glp-2 avec un autre agent therapeutique dans les maladies des os |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP01982302A Expired - Lifetime EP1326630B1 (fr) | 2000-09-18 | 2001-09-17 | Utilisation de peptides glp-2 |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP01967517A Expired - Lifetime EP1414486B1 (fr) | 2000-09-18 | 2001-09-18 | Utilisation de glp-2 avec un autre agent therapeutique dans les maladies des os |
Country Status (11)
Country | Link |
---|---|
US (2) | US6770620B2 (fr) |
EP (3) | EP1326630B1 (fr) |
JP (2) | JP5161412B2 (fr) |
AT (2) | ATE396738T1 (fr) |
AU (2) | AU2002213925A1 (fr) |
CY (2) | CY1108263T1 (fr) |
DE (2) | DE60134251D1 (fr) |
DK (2) | DK1326630T3 (fr) |
ES (2) | ES2310192T3 (fr) |
PT (2) | PT1326630E (fr) |
WO (2) | WO2002022151A2 (fr) |
Families Citing this family (63)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7186683B2 (en) * | 2000-09-18 | 2007-03-06 | Sanos Bioscience A/S | Use of GLP for the treatment, prevention, diagnosis, and prognosis of bone-related and nutrition-related disorders |
US20070135345A1 (en) * | 2000-09-18 | 2007-06-14 | Henriksen Dennis B | Use of GLP-2 for the treatment or prevention, of bone-related disorders |
US7371721B2 (en) * | 2000-09-18 | 2008-05-13 | Sanos Bioscience A/S | Use of GLP-2 and related compounds for the treatment, prevention, diagnosis, and prognosis of bone-related disorders and calcium homeostasis related syndromes |
ATE396738T1 (de) * | 2000-09-18 | 2008-06-15 | Sanos Bioscience As | Verwendung von glp-2-peptiden |
US20080249016A1 (en) * | 2000-09-18 | 2008-10-09 | Sanos Bioscience A/S | Use of GLP-2 in a combination treatment for bone-related disorders |
RO120121B1 (ro) * | 2000-12-18 | 2005-09-30 | Elena Ionaşcu | Soluţie injectabilă, cu efect antiinflamator, procedeu de obţinere şi metodă de tratament a bolilor autoimune |
CA2347330C (fr) * | 2001-05-10 | 2002-03-12 | Pharmaceutical Partners Of Canada Inc. | Preparation injectable liquide de pamidronate disodique |
DE10135315A1 (de) * | 2001-07-19 | 2003-01-30 | Bayer Ag | Stents |
DK1463751T3 (da) | 2001-12-21 | 2013-08-26 | Human Genome Sciences Inc | Albuminfusionsproteiner. |
CN1320886C (zh) | 2002-05-17 | 2007-06-13 | 杜克大学 | 安非他酮与抗惊厥药在制备治疗肥胖症的药物的用途 |
US20050215552A1 (en) * | 2002-05-17 | 2005-09-29 | Gadde Kishore M | Method for treating obesity |
WO2004084859A2 (fr) * | 2003-03-21 | 2004-10-07 | Nastech Pharmaceutical Company Inc. | Formulations nasales de calcitonine contenant du chlorobutanol |
WO2004085471A2 (fr) * | 2003-03-24 | 2004-10-07 | Novo Nordisk A/S | Derives de glp-2 |
EP1870096A3 (fr) * | 2003-04-29 | 2011-04-20 | Orexigen Therapeutics, Inc. | Compositions pour influencer la perte de poids |
DK2316456T3 (en) * | 2003-04-29 | 2017-09-11 | Orexigen Therapeutics Inc | Compositions for affecting weight loss comprising an opioid antagonist and bupropion |
ATE549028T1 (de) | 2003-05-15 | 2012-03-15 | Tufts College | Stabile analoga von glp-1 |
EP1734955A2 (fr) * | 2004-01-13 | 2006-12-27 | Duke University | Compositions anticonvulsives, medicament antipsychotique et leurs methodes d'utilisation permettant d'influer sur la perte de poids |
US7713959B2 (en) * | 2004-01-13 | 2010-05-11 | Duke University | Compositions of an anticonvulsant and mirtazapine to prevent weight gain |
BRPI0510593A (pt) * | 2004-05-03 | 2007-11-20 | Univ Duke | composições para afetar a perda de peso |
EA014184B1 (ru) | 2005-05-04 | 2010-10-29 | Зеаланд Фарма А/С | Аналоги глюкагонподобного пептида-2 (glp-2) |
WO2006135660A2 (fr) * | 2005-06-10 | 2006-12-21 | University Of Chicago | Therapies faisant intervenir le recepteur beta de lymphotoxine |
EP3132792B1 (fr) * | 2005-11-22 | 2019-09-11 | Nalpropion Pharmaceuticals, Inc. | Composition et procédés d'augmentation de la sensibilité d'insuline |
WO2007089318A2 (fr) * | 2005-11-23 | 2007-08-09 | Orexigen Therapeutics, Inc. | Compositions et méthodes de réduction de la boulimie |
AU2007249736A1 (en) * | 2006-05-15 | 2007-11-22 | Wisconsin Alumni Research Foundation | Pulmonary delivery of 1alpha,25-dihydroxyvitamin D3 and co-administration of parathyroid hormone or calcitonin |
US8916195B2 (en) | 2006-06-05 | 2014-12-23 | Orexigen Therapeutics, Inc. | Sustained release formulation of naltrexone |
CN101573376B (zh) | 2006-11-08 | 2013-11-06 | 西兰制药公司 | 选择性胰高血糖素样肽-2(glp-2)类似物 |
KR101654176B1 (ko) | 2006-11-09 | 2016-09-09 | 오렉시젠 세러퓨틱스 인크. | 신속하게 용해되는 중간층을 포함하는 층상의 약제학적 제형 |
KR20170077291A (ko) * | 2006-11-09 | 2017-07-05 | 오렉시젠 세러퓨틱스 인크. | 단위 용량 팩키지 |
AU2008228903B2 (en) | 2007-03-19 | 2013-03-07 | Vita Sciences, Llc | Transdermal patch and method for delivery of vitamin B12 |
AU2008297566A1 (en) * | 2007-09-11 | 2009-03-19 | Mondobiotech Laboratories Ag | Use of a peptide as a therapeutic agent |
JP2011521973A (ja) | 2008-05-30 | 2011-07-28 | オレキシジェン・セラピューティクス・インコーポレーテッド | 内臓脂肪の状態を処置するための方法 |
US20110171164A1 (en) * | 2008-09-19 | 2011-07-14 | Nektar Therapeutics | Polymer conjugates of glp-2-like peptides |
EP2350118B1 (fr) | 2008-09-19 | 2016-03-30 | Nektar Therapeutics | Polymères à base de glucide pour administration de médicaments et leurs conjugués |
HUE037449T2 (hu) | 2008-10-17 | 2018-08-28 | Sanofi Aventis Deutschland | Egy inzulin és egy GLP-1 agonista kombinációja |
US9301938B2 (en) | 2009-09-23 | 2016-04-05 | Biokier, Inc. | Composition and method for treatment of diabetes |
EP2311486A1 (fr) * | 2009-10-07 | 2011-04-20 | Nestec S.A. | GLP-2 en utilisation pour la récupération intestinale et musculaire |
PE20121316A1 (es) | 2009-11-13 | 2012-10-05 | Sanofi Aventis Deutschland | Composicion farmaceutica que comprende un agonista de glp-1 y metionina |
RU2537239C2 (ru) | 2009-11-13 | 2014-12-27 | Санофи-Авентис Дойчланд Гмбх | Фармацевтическая композиция, включающая агонист glp-1, инсулин и метионин |
AU2011203867B2 (en) | 2010-01-11 | 2015-12-03 | Nalpropion Pharmaceuticals Llc | Methods of providing weight loss therapy in patients with major depression |
AU2011202239C1 (en) | 2010-05-19 | 2017-03-16 | Sanofi | Long-acting formulations of insulins |
PT2611458T (pt) | 2010-08-30 | 2016-12-16 | Sanofi Aventis Deutschland | Utilização de ave0010 para o fabrico de um medicamento para o tratamento da diabetes mellitus tipo 2 |
US9821032B2 (en) | 2011-05-13 | 2017-11-21 | Sanofi-Aventis Deutschland Gmbh | Pharmaceutical combination for improving glycemic control as add-on therapy to basal insulin |
CN103889457A (zh) * | 2011-05-24 | 2014-06-25 | 波利威乐赞助有限公司 | 使用特异性的基于壳聚糖的纳米复合物用于有效并安全递送siRNA的组合物和方法 |
PT2750699E (pt) | 2011-08-29 | 2015-11-03 | Sanofi Aventis Deutschland | Acelerómetro pendular |
TWI559929B (en) | 2011-09-01 | 2016-12-01 | Sanofi Aventis Deutschland | Pharmaceutical composition for use in the treatment of a neurodegenerative disease |
EA028929B1 (ru) | 2012-05-03 | 2018-01-31 | Зилэнд Фарма А/С | Аналоги глюкагоноподобного пептида-2 (glp-2) |
ES2802048T3 (es) | 2012-06-06 | 2021-01-15 | Nalpropion Pharmaceuticals Llc | Composición para uso en un método para el tratamiento de sobrepeso y obesidad en pacientes con alto riesgo cardiovascular |
HUE042381T2 (hu) | 2013-04-03 | 2019-06-28 | Sanofi Sa | Cukorbetegség kezelése hosszan ható inzulinkészítményekkel |
WO2015016682A1 (fr) * | 2013-08-01 | 2015-02-05 | 경희대학교 산학협력단 | Composition pharmaceutique destinée a prévenir ou à traiter le diabète sucré, procédé de prévention ou de traitement du diabète sucré, et procédé de dépistage d'agent thérapeutique du diabète sucré |
US10493042B2 (en) | 2013-08-01 | 2019-12-03 | University-Industry Cooperation Group Of Kyung Hee University | Method for preventing or treating diabetes mellitus, and method for screening for diabetes mellitus therapeutic agent |
US8969371B1 (en) | 2013-12-06 | 2015-03-03 | Orexigen Therapeutics, Inc. | Compositions and methods for weight loss in at risk patient populations |
CA2970200A1 (fr) | 2014-12-12 | 2016-06-16 | Sanofi-Aventis Deutschland Gmbh | Formulation contenant un rapport fixe d'insuline glargine/lixisenatide |
TWI748945B (zh) | 2015-03-13 | 2021-12-11 | 德商賽諾菲阿凡提斯德意志有限公司 | 第2型糖尿病病患治療 |
TW201705975A (zh) | 2015-03-18 | 2017-02-16 | 賽諾菲阿凡提斯德意志有限公司 | 第2型糖尿病病患之治療 |
US10744070B2 (en) | 2015-06-19 | 2020-08-18 | University Of Southern California | Enteral fast access tract platform system |
WO2016205754A1 (fr) | 2015-06-19 | 2016-12-22 | University Of Southern California | Compositions et procédés pour l'administration de nutriments modifiés |
WO2018009778A1 (fr) * | 2016-07-07 | 2018-01-11 | Baylor College Of Medicine | Combinaison de glp-1 et de glp-2 pour le traitement ou la prévention de maladies, troubles et syndromes métaboliques |
US10774127B2 (en) | 2016-10-12 | 2020-09-15 | University Of Copenhagen | Peptide dual agonists of GIPR and GLP2R |
CN117384274A (zh) | 2016-12-09 | 2024-01-12 | 西兰制药公司 | 酰化的glp-1/glp-2双重激动剂 |
EP3694537A1 (fr) | 2017-10-12 | 2020-08-19 | University of Copenhagen | Polythérapie pour le traitement de maladies des os |
US20210187077A1 (en) * | 2019-12-23 | 2021-06-24 | Idaho State University | GLP-1 Agonist Conjugates for Sustained Glycemic Control |
JP2023508175A (ja) * | 2019-12-24 | 2023-03-01 | ハンミ ファーマシューティカル カンパニー リミテッド | Glp-2又はその結合体を含む、代謝性骨疾患の予防又は治療用薬学的組成物 |
CN116437967A (zh) * | 2020-09-25 | 2023-07-14 | 韩美药品株式会社 | 包括对胰高血糖素、glp-1和glp受体全部具有活性的三重激动剂或其缀合物的用于预防或治疗骨病的药物组合物 |
Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1987006941A1 (fr) | 1986-05-05 | 1987-11-19 | The General Hospital Corporation | Hormone insulinotrope |
WO1990011296A1 (fr) | 1989-03-20 | 1990-10-04 | The General Hospital Corporation | Hormone insulinotrope |
WO1991011457A1 (fr) | 1990-01-24 | 1991-08-08 | Buckley Douglas I | Analogues de glp-1 utiles dans le traitement du diabete |
WO1997031943A1 (fr) * | 1996-03-01 | 1997-09-04 | Novo Nordisk A/S | Utilisation d'une composition pharmaceutique contenant un peptide visant a reduire l'appetit |
WO1998052600A1 (fr) * | 1997-05-16 | 1998-11-26 | 1149336 Ontario Inc. | Methodes permettant d'ameliorer le fonctionnement du tractus gastro-intestinal superieur |
US6077949A (en) | 1996-12-13 | 2000-06-20 | Allelix Biopharmaceuticals, Inc. | Cloned glucagon-like peptide 2 receptors |
WO2002024214A2 (fr) * | 2000-09-18 | 2002-03-28 | Osteometer Biotech A/S | Utilisation de glp dans le cadre du traitement, de la prevention, du diagnostic et du pronostic de troubles en rapport avec les os ou l'alimentation |
Family Cites Families (41)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
PT101031B (pt) | 1991-11-05 | 2002-07-31 | Transkaryotic Therapies Inc | Processo para o fornecimento de proteinas por terapia genetica |
US5512459A (en) | 1993-07-20 | 1996-04-30 | Bionebraska, Inc. | Enzymatic method for modification or recombinant polypeptides |
US5789379A (en) | 1995-04-14 | 1998-08-04 | Allelix Biopharmaceutical Inc. | Glucagon-like peptide-2 analogs |
US5834428A (en) | 1995-04-14 | 1998-11-10 | 1149336 Ontario Inc. | Glucagon-like peptide-2 and its therapeutic use |
US5990077A (en) | 1995-04-14 | 1999-11-23 | 1149336 Ontario Inc. | Glucagon-like peptide-2 and its therapeutic use |
US6184201B1 (en) | 1995-04-14 | 2001-02-06 | Nps Allelix Corp. | Intestinotrophic glucagon-like peptide-2 analogs |
US5912229A (en) | 1996-03-01 | 1999-06-15 | Novo Nordisk Als | Use of a pharmaceutical composition comprising an appetite-suppressing peptide |
ATE227309T1 (de) | 1996-04-12 | 2002-11-15 | Ontario Inc 1149336 | Analoge des glucagon ähnlichen peptides -2 |
CA2258307C (fr) | 1996-07-05 | 2008-02-12 | Novo Nordisk A/S | Methode de production de polypeptides heterologues a chaines courtes au moyen de cellules de levure presentant une activite reduite de protease yap3 |
US5994500A (en) | 1996-07-19 | 1999-11-30 | 1149336 Ontario Inc. | Antagonists of intestinotrophic GLP-2 peptides |
AU4112497A (en) | 1996-08-30 | 1998-03-19 | Novo Nordisk A/S | Glp-2 derivatives |
US6011155A (en) * | 1996-11-07 | 2000-01-04 | Novartis Ag | N-(substituted glycyl)-2-cyanopyrrolidines, pharmaceutical compositions containing them and their use in inhibiting dipeptidyl peptidase-IV |
WO1998024813A2 (fr) | 1996-12-06 | 1998-06-11 | Amgen Inc. | Facteurs de croissance des keratinocytes et leurs utilisations |
US5952301A (en) | 1996-12-10 | 1999-09-14 | 1149336 Ontario Inc. | Compositions and methods for enhancing intestinal function |
DK0946591T3 (da) | 1996-12-13 | 2007-08-13 | Nps Allelix Corp | Klonede glucagon-lignende peptid-2 receptorer |
US6051557A (en) | 1997-05-16 | 2000-04-18 | 1149336 Ontario Inc. | Methods of enhancing functioning of the upper gastrointestinal tract |
WO1999006059A2 (fr) | 1997-07-30 | 1999-02-11 | Board Of Regents, The University Of Texas System | Procedes et compositions relatifs a la cytotoxicite induite par l'oxyde nitrique |
ES2222613T3 (es) | 1997-09-12 | 2005-02-01 | Pharis Biotec Gmbh | Composicion para la terapia de diabetes mellitus y de la obesidad. |
AU2149899A (en) | 1998-01-23 | 1999-08-09 | Novo Nordisk A/S | Process for making desired polypeptides in yeast |
ES2288807T1 (es) | 1998-02-02 | 2008-02-01 | Trustees Of Tufts College | Uso de inhibidores de dipeptidasa para regular el metabolismo de la glucosa. |
AU2712899A (en) | 1998-02-27 | 1999-09-15 | Novo Nordisk A/S | Glp-2 derivatives with helix-content exceeding 25 percent, forming partially structured micellar-like aggregates |
EP1062229A1 (fr) | 1998-03-09 | 2000-12-27 | Zealand Pharmaceuticals A/S | Conjugues peptidiques pharmacologiquement actifs ayant une tendance reduite a l'hydrolyse enzymatique |
FR2777283B1 (fr) * | 1998-04-10 | 2000-11-24 | Adir | Nouveaux composes peptidiques analogues du glucagon-peptide- 1 (7-37), leur procede de preparation et les compositions pharmaceutiques qui les contiennent |
WO1999058144A1 (fr) | 1998-05-11 | 1999-11-18 | 1149336 Ontario Inc. | Procedes d'amelioration du fonctionnement du gros intestin |
IL141471A0 (en) | 1998-08-21 | 2002-03-10 | Point Therapeutics Inc | Regulation of substrate activity |
US6193997B1 (en) | 1998-09-27 | 2001-02-27 | Generex Pharmaceuticals Inc. | Proteinic drug delivery system using membrane mimetics |
EP1119625B1 (fr) | 1998-10-07 | 2005-06-29 | Medical College Of Georgia Research Institute, Inc. | Peptide glucodependant insulinotrope utilise comme hormone osteotrope |
AU1525700A (en) * | 1998-11-19 | 2000-06-05 | Board Of Trustees Of The University Of Arkansas, The | Increasing bone strength with selected bisphosphonates |
PL205713B1 (pl) * | 1998-12-07 | 2010-05-31 | Sod Conseils Rech Applic | Związki stanowiące analogi GLP-1, kompozycje farmaceutyczne zawierające takie związki oraz zastosowanie tych związków |
PL202367B1 (pl) * | 1998-12-07 | 2009-06-30 | Sod Conseils Rech Applic | Związki stanowiące analogi GLP-1, kompozycje zawierające te związki oraz zastosowanie tych związków |
CO5150173A1 (es) | 1998-12-10 | 2002-04-29 | Novartis Ag | Compuestos n-(glicilo sustituido)-2-cianopirrolidinas inhibidores de peptidasa de dipeptidilo-iv (dpp-iv) los cuales son efectivos en el tratamiento de condiciones mediadas por la inhibicion de dpp-iv |
US6271200B1 (en) | 1998-12-21 | 2001-08-07 | Generex Pharmaceuticals Inc. | Proteinic drug delivery system using aerosolized membrane-mimetic amphiphiles |
WO2000042026A1 (fr) | 1999-01-15 | 2000-07-20 | Novo Nordisk A/S | Agonistes non peptidiques de glp-1 |
GB9905416D0 (en) | 1999-03-09 | 1999-05-05 | Allelix Biopharma | Small molecules having GLP-2 like activity |
US6110949A (en) * | 1999-06-24 | 2000-08-29 | Novartis Ag | N-(substituted glycyl)-4-cyanothiazolidines, pharmaceutical compositions containing them and their use in inhibiting dipeptidyl peptidase-IV |
EP1076066A1 (fr) | 1999-07-12 | 2001-02-14 | Zealand Pharmaceuticals A/S | Peptides abaissant le taux de glucose sanguin |
WO2001041779A2 (fr) | 1999-12-08 | 2001-06-14 | 1149336 Ontario Inc. | Traitement relatif a la chimiotherapie |
US20020061838A1 (en) * | 2000-05-17 | 2002-05-23 | Barton Holmquist | Peptide pharmaceutical formulations |
HU229108B1 (en) * | 2000-06-16 | 2013-09-30 | Lilly Co Eli | Glucagon-like peptide-1 analogs |
EP1305338A2 (fr) * | 2000-08-02 | 2003-05-02 | Theratechnologies Inc. | Peptides biologiques modifies presentant une activite renforcee |
WO2002066062A2 (fr) * | 2001-02-01 | 2002-08-29 | Drucker Daniel J | Renforcement de l'activite de glp-2 |
-
2001
- 2001-09-17 AT AT01982302T patent/ATE396738T1/de active
- 2001-09-17 PT PT01982302T patent/PT1326630E/pt unknown
- 2001-09-17 JP JP2002526401A patent/JP5161412B2/ja not_active Expired - Fee Related
- 2001-09-17 EP EP01982302A patent/EP1326630B1/fr not_active Expired - Lifetime
- 2001-09-17 DK DK01982302T patent/DK1326630T3/da active
- 2001-09-17 US US09/954,304 patent/US6770620B2/en not_active Expired - Fee Related
- 2001-09-17 WO PCT/EP2001/010714 patent/WO2002022151A2/fr active IP Right Grant
- 2001-09-17 DE DE60134251T patent/DE60134251D1/de not_active Expired - Lifetime
- 2001-09-17 ES ES01982302T patent/ES2310192T3/es not_active Expired - Lifetime
- 2001-09-17 EP EP08156283A patent/EP1970072A1/fr not_active Withdrawn
- 2001-09-17 AU AU2002213925A patent/AU2002213925A1/en not_active Abandoned
- 2001-09-18 PT PT01967517T patent/PT1414486E/pt unknown
- 2001-09-18 AU AU2001287892A patent/AU2001287892A1/en not_active Abandoned
- 2001-09-18 EP EP01967517A patent/EP1414486B1/fr not_active Expired - Lifetime
- 2001-09-18 ES ES01967517T patent/ES2345874T3/es not_active Expired - Lifetime
- 2001-09-18 WO PCT/GB2001/004178 patent/WO2002024214A2/fr active Application Filing
- 2001-09-18 AT AT01967517T patent/ATE466592T1/de active
- 2001-09-18 JP JP2002528284A patent/JP5189723B2/ja not_active Expired - Fee Related
- 2001-09-18 DK DK01967517.2T patent/DK1414486T3/da active
- 2001-09-18 DE DE60142084T patent/DE60142084D1/de not_active Expired - Lifetime
-
2003
- 2003-03-18 US US10/391,460 patent/US6943151B2/en not_active Expired - Fee Related
-
2008
- 2008-08-13 CY CY20081100866T patent/CY1108263T1/el unknown
-
2010
- 2010-07-30 CY CY20101100721T patent/CY1110721T1/el unknown
Patent Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1987006941A1 (fr) | 1986-05-05 | 1987-11-19 | The General Hospital Corporation | Hormone insulinotrope |
WO1990011296A1 (fr) | 1989-03-20 | 1990-10-04 | The General Hospital Corporation | Hormone insulinotrope |
WO1991011457A1 (fr) | 1990-01-24 | 1991-08-08 | Buckley Douglas I | Analogues de glp-1 utiles dans le traitement du diabete |
WO1997031943A1 (fr) * | 1996-03-01 | 1997-09-04 | Novo Nordisk A/S | Utilisation d'une composition pharmaceutique contenant un peptide visant a reduire l'appetit |
US6077949A (en) | 1996-12-13 | 2000-06-20 | Allelix Biopharmaceuticals, Inc. | Cloned glucagon-like peptide 2 receptors |
WO1998052600A1 (fr) * | 1997-05-16 | 1998-11-26 | 1149336 Ontario Inc. | Methodes permettant d'ameliorer le fonctionnement du tractus gastro-intestinal superieur |
WO2002024214A2 (fr) * | 2000-09-18 | 2002-03-28 | Osteometer Biotech A/S | Utilisation de glp dans le cadre du traitement, de la prevention, du diagnostic et du pronostic de troubles en rapport avec les os ou l'alimentation |
Non-Patent Citations (30)
Title |
---|
BELL, G. I. ET AL., NATURE, vol. 304, 1983, pages 368 - 371 |
BUHL ET AL., J. BIOL. CHEM., vol. 263, no. 18, 1988, pages 8621 |
CHEESEMAN; TSENG, AMERICAN JOURNAL OF PHYSIOLOGY, 1996, pages 271G477 - G482 |
DRUCKER ET AL., PNAS: USA, vol. 93, 1996, pages 7911 - 7916 |
DRUCKER, D. J. ET AL., PROC NATL ACAD SCI USA, vol. 93, no. 15, 1996, pages 7911 - 7916 |
GRAHAM, D. Y. ET AL., ALIMENT PHARMACOL THER, vol. 4, 1999, pages 515 - 9 |
GUTNIAK, M., N ENGL. J. MED., vol. 326, 1992, pages 1316 - 22 |
HABENER, J. F., DIABETES MELLITUS, 1996, pages 68 - 78 |
HABENER, J.F., DIABETES MELLITUS, 1996, pages 68 - 78 |
HARTMANN B ET AL., PEPTIDES, vol. 21, no. 1, 2000, pages 73 - 80 |
HARTMANN, B. ET AL., J CLINENDOCRINOL METAB, vol. 85, no. 8, 2000, pages 2884 - 2888 |
HENDRIKSE, J. ET AL., ASBMR-IBMS SECOND |
IRWIN; WONG, MOL. ENDOCRINOL., vol. 9, no. 3, 1995, pages 267 - 77 |
JEPPESEN, P. B. ET AL., GUT, vol. 47, no. 3, 2000, pages 370 - 376 |
JOHNELL, 0. ET AL., ASBMR-IBMS SECOND JOINT MEETING, pages S170 |
JORNVALL ET AL., FEBS LETT, vol. 123, 1981, pages 205 |
MOJSOV, S., INT. J. PEPTIDE PROTEIN RESEARCH, vol. 40, 1992, pages 333 - 343 |
MUNROE, D. G. ET AL., PROC NATL ACAD SCI U S A, vol. 96, no. 4, 1999, pages 1569 - 1573 |
NAUCK, M. A. ET AL., J CLINENDOCRINOL METAB, vol. 76, no. 4, 1993, pages 912 - 917 |
NISHI; STEINER, MOL. ENDOCRINOL., vol. 4, 1990, pages 1192 - 8 |
P.B. ET AL.: "Gastroenterology", PRESS |
REID, I. R. ET AL., THE AMERICAN PHYSIOLOGICAL SOCIETY, 1993, pages E655 - E659 |
SCHLEMMER, A. ET AL., EUR. J. ENDOCRINOL., vol. 140, 1999, pages 332 - 337 |
STOLK, R. P. ET AL., BONE, vol. 6, 1996, pages 545 - 549 |
THOMAS, D. M. ET AL., BONE, vol. 23, 1993, pages 181 - 186 |
THOMAS, D. M. ET AL., J. BONE MINER. RES., vol. 11, 1996, pages 1312 - 1320 |
THULESEN, J. ET AL.: "Gut.", PRESS |
TSAI, C. H. ET AL., AM J PHYSIOL, vol. 273, 1997, pages E77 - E84 |
WO DEMANN, M. ET AL., SCAND J GASTROENTEROL, vol. 33, no. 8, 1998, pages 828 - 832 |
WOJDEMANN, M. ET AL., JCLIN ENDOCRINOL METAB, vol. 84, no. 7, 1999, pages 2513 - 2517 |
Also Published As
Publication number | Publication date |
---|---|
ATE466592T1 (de) | 2010-05-15 |
ATE396738T1 (de) | 2008-06-15 |
JP2004524268A (ja) | 2004-08-12 |
DK1326630T3 (da) | 2008-09-15 |
JP2004508410A (ja) | 2004-03-18 |
CY1110721T1 (el) | 2015-06-10 |
PT1326630E (pt) | 2008-09-02 |
JP5161412B2 (ja) | 2013-03-13 |
EP1414486B1 (fr) | 2010-05-05 |
US20040082507A1 (en) | 2004-04-29 |
ES2345874T3 (es) | 2010-10-05 |
DE60142084D1 (de) | 2010-06-17 |
WO2002022151A2 (fr) | 2002-03-21 |
US20020037836A1 (en) | 2002-03-28 |
JP5189723B2 (ja) | 2013-04-24 |
AU2002213925A1 (en) | 2002-03-26 |
ES2310192T3 (es) | 2009-01-01 |
DK1414486T3 (da) | 2010-08-30 |
WO2002024214A3 (fr) | 2004-02-19 |
PT1414486E (pt) | 2010-07-21 |
US6943151B2 (en) | 2005-09-13 |
DE60134251D1 (de) | 2008-07-10 |
EP1326630B1 (fr) | 2008-05-28 |
WO2002024214A2 (fr) | 2002-03-28 |
WO2002022151A3 (fr) | 2003-03-13 |
US6770620B2 (en) | 2004-08-03 |
EP1414486A2 (fr) | 2004-05-06 |
EP1326630A2 (fr) | 2003-07-16 |
AU2001287892A1 (en) | 2002-04-02 |
CY1108263T1 (el) | 2014-02-12 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US6943151B2 (en) | Method of inhibiting bone resorption and/or promoting bone formation using GLP-2 and related compounds | |
Estall et al. | Glucagon-like peptide-2 | |
US7371721B2 (en) | Use of GLP-2 and related compounds for the treatment, prevention, diagnosis, and prognosis of bone-related disorders and calcium homeostasis related syndromes | |
EP1988100B1 (fr) | Dérivés du peptide-2 analogue au glucagon et leurs utilisations therapeutiques | |
Lafferty et al. | Proglucagon-derived peptides as therapeutics | |
JP6989385B2 (ja) | アシル化グルカゴン類似体 | |
CN102389413B (zh) | 用于治疗糖尿病的组合物及其应用 | |
Vianna et al. | effects of type 2 diabetes therapies on bone metabolism | |
US7176182B2 (en) | Methods of enhancing functioning of the large intestine | |
TW201202265A (en) | Glucagon analogues | |
CN104583234A (zh) | 毒蜥外泌肽-4肽类似物 | |
CN108026153A (zh) | 作为选择性肽双重glp-1/胰高血糖素受体激动剂的新毒蜥外泌肽-4衍生物 | |
CN103429742A (zh) | 用于治疗内分泌、胃肠或自体免疫性疾病的组合物和方法 | |
JP2005523877A (ja) | 重病に関連する死亡率および罹患率の低減化方法 | |
Stensen et al. | GIP and the gut-bone axis–Physiological, pathophysiological and potential therapeutic implications | |
Yavropoulou et al. | Incretins and bone: evolving concepts in nutrient-dependent regulation of bone turnover | |
Conlon et al. | Dual-agonist incretin peptides from fish with potential for obesity-related Type 2 diabetes therapy–A review | |
US10842851B2 (en) | Relaxin for treating patients afflicted of impaired glucose tolerance | |
US20080249016A1 (en) | Use of GLP-2 in a combination treatment for bone-related disorders | |
WO1999058144A1 (fr) | Procedes d'amelioration du fonctionnement du gros intestin | |
Riar et al. | Glycemic impact of metformin in diabetes caused by heterozygous insulin gene mutation R46Q | |
Young et al. | Drugs for metabolic bone disease | |
Ganeva | SAFETY PROFILE OF DIPEPTIDYL PEPTIDASE-4 INHIBITORS | |
CN101138631A (zh) | 一种新型的重组甲状旁腺素(1-34)相关肽的滴鼻剂 | |
Liu et al. | Effect of gut hormones on bone metabolism and their possible mechanisms in the treatment of osteoporosis |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
Free format text: ORIGINAL CODE: 0009012 |
|
AC | Divisional application: reference to earlier application |
Ref document number: 1326630 Country of ref document: EP Kind code of ref document: P |
|
AK | Designated contracting states |
Kind code of ref document: A1 Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE TR |
|
17P | Request for examination filed |
Effective date: 20090302 |
|
AKX | Designation fees paid |
Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE TR |
|
17Q | First examination report despatched |
Effective date: 20090526 |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN |
|
18D | Application deemed to be withdrawn |
Effective date: 20140401 |